Carbodefluorination of fluoroalkyl ketones via a carbene-initiated rearrangement strategy

The C–F bond cleavage and C–C bond formation (i.e., carbodefluorination) of readily accessible (per)fluoroalkyl groups constitutes an atom-economical and efficient route to partially fluorinated compounds. However, the selective mono-carbodefluorination of trifluoromethyl (CF3) groups remains a challenge, due to the notorious inertness of C–F bond and the risk of over-defluorination arising from C–F bond strength decrease as the defluorination proceeds. Herein, we report a carbene-initiated rearrangement strategy for the carbodefluorination of fluoroalkyl ketones with β,γ-unsaturated alcohols to provide skeletally and functionally diverse α-mono- and α,α-difluoro-γ,δ-unsaturated ketones. The reaction starts with the formation of silver carbenes from fluoroalkyl N-triftosylhydrazones, followed by nucleophilic attack of a β,γ-unsaturated alcohol to form key silver-coordinated oxonium ylide intermediates, which triggers selective C–F bond cleavage by HF elimination and C–C bond formation through Claisen rearrangement of in situ generated difluorovinyl ether. The origin of chemoselectivity and the reaction mechanism are determined by experimental and DFT calculations. Collectively, this strategy by an intramolecular cascade process offers significant advances over existing stepwise strategies in terms of selectivity, efficiency, functional group tolerance, etc.

Bi and co-workers reported a formal selective C-F bond allylation/allenylation of trifluoromethylhydrazones by Ag-catalysis to access a diverse range of α,α-difluoroalkylketones featuring heterocycles or alkene/allene moiety. A cascading process including Ag-mediated defluorinative oxygenation and fluorine-Claisen rearrangement was supposed as the success of the reaction, which is distinct form the well-known single electron manifold employed for analogous transformation of trifluoromethyl carbonyls. Significantly broad substrate scope was demonstrated with respect to both of the coupling partners. Also, the gram scale reaction and elaboration of the products highlight the synthetic potency of this reaction. Interestingly, control experiments and DFT calculation reveal the dual role of Ag catalyst to enable the formation of gem-difluoroalkene intermediate and facilitate the subsequent Claisen rearrangement. Overall, this review supports the publication of manuscript in Nat. Commun., after some revisions were addressed.
(1) Does fluorine atoms exert a positive effect on the [3,3]-rearrangement of gem-difluorovinyl ether? Could the reaction proceed under the same conditions when replacing fluoride with chloride or bromide?
(3) In Figure 2, only indole, benzofurans, benzothiophenes, pyrrole, furan and thiophene derived carbinols were presented, what about substrates with greater degree of aromaticity, such as benzyl alcohol or naphthalene carbinol? (4) The authors are suggested to comment on the driving force for the [3,3]-rearrangement which destroy the aromaticity of the substrate. Why the dearomatized products did not undergo rearrangement spontaneously to regain aromaticity? (5) All presented alcohol substrates were primary and secondary alcohols, are tertiary alcohols viable substrates? (6) Aside from alcohols, are other nucleophiles, such as amine and thiol suitable for this carbene insertion/rearrangement cascade? (7) In the DFT part, the calculation result showed that the weak coordination of silver and oxygen could lower the energy barrier for the rate-determining rearrangement step. Could other stronger Lewis acids be applied instead of sliver to further reduce the rearrangement energy barrier, resulting in even milder reaction conditions for the [3,3]-rearrangement of gem-difluorovinyl ether? (8) While N-triftosylhydrazone substrates derived from alkyl trifluoromethyl ketones reacted with β,γunsaturated alcohols readily, no such a case was demonstrated in Fig. 2 when reacted with heteroaryl carbinols, why? (8) In cases 177-182, why Rh2(esp)2 exhibited higher efficiency than TpBr3 Ag? Does any alkene product derived from deprotonation of silver carbene was observed? (9) In Feng's work (ACIE 2021, 60, 20237), the [3,3]-rearrangement tend to yield CF2-bridged 1,5diene product. However, in this work, transformation of 3 to 198, gem-difluoroalkene was obtained as the rearranged product, Please provide an explanation for this. (10) Last sentence of the abstract, "…in term of…" should be "… in terms of…".
Reviewer #2 (Remarks to the Author): Very recently the synthesis of fluorinated organic compounds using the acyl-CF3 compounds (CF3C(O)R) as fluorine source through carbodefluorination strategy has received a great attention and big progress has been made. But I think this strategy is meaningless because acyl-CF3 compounds are not easily prepared. That is: the introduction of fluorine atom into organic compounds was a challenging and hard, although the chemistry of the selective defluorination is interesting, the synthesis of new fluorinated compound through defluorination of fluorinated compounds was the waste of fluorine source. In this manuscript, Bi and co-workers described the carbodefluorination of acyl-CF3 compounds via fluoroalkyl N-triftosylhydrazones. This reaction proceeded though the silvercatalyzed sequential carbene generation, oxonium ylide formation, C-F bond cleavage, and eventual C-C bond formation through Claisen rearrangement of the resultant difluorovinyl ethers. A broad range of (hetero)aryl/alkyl fluoroalkyl ketones and β,γ-unsaturated alcohols were amenable to this reaction. This silver-catalyzed protocol provided single-step access to skeletally and functionally diverse α-mono-and α,α-difluoro-γ,δ-unsaturated ketones. The chemistry described in this manuscript is novel and interesting. Furthermore this manuscript was organized and written well. As I mentioned above, this method has less potential application in medicinal chemistry. But in light of the novelty of chemistry, I recommended for publication of this manuscript in Nature Communications when the following comments were addressed. 1) The title of this manuscript was too general. What kind of compound for carbodefluorination should be given.
2) How about the reaction of N-triftosylhydrazones derived from alkyl trifluoromethyl ketone with (hetero)aromatic carbinols, please give some examples.
3) Regarding to the reaction mechanism, the authors stated that gem-difluorinated vinyl ether was formed from the HF elimination of oxonium ylide. It may be formed from the elimiantion of AgF from oxonium ylide. Please confirm this by experiments.

Reviewer #3 (Remarks to the Author):
This manuscript by Bi and coworkers details a C-F functionalization of trifluoroacyl groups to a wide range of difluoro allyllic structures. The manuscript showcases the applicability of this reaction to construct an impressive and diverse range of structural motives by applying either various heterocycles, allylic alcohols or propargylic alcohols as reaction partners. The functional group tolerance of this transformation is good and a large amount of products was included in the scope to demonstrate the utility. A mechanism was proposed, that was also probed by DFT computations. From the synthetic point I recommend publication of this manuscript in Nature Comms, however, I do have some reservations about the computational aspects of this work in the current state. Mostly, the method combination B3LYP/6-31G(d,p) really is outdated for relative reaction (free) energies. Firstly, there is no reason not to apply empirical dispersion correction (D3) as it comes for free and has been shown countless times to systematically improve energies with B3LYP and many other functionals, particularly for non-covalent interactions. This is of relevance to this work because the authors invoke non-covalent interactions to explain parts of the mechanism. Moreover, energies at the double-zeta level are less accurate than those obtained with a larger basis set, which is why single point calculations on the stationary points with a triple-zeta basis set are the commonly used standard procedure. Thus, I urge the authors to improve the relative (free) energies for the reaction profile. Possibly this will not change the overall conclusions from the calculations, but it will make the reaction barriers that the authors also quote in the text much more reliable. Furthermore, I would appreciate the analysis of alternative reaction mechanisms in order to further back up the proposed mechanism. Alternatives that come to mind include: -beta-F-elimination from Int2 -deprotonation of Int2 (the O-H+ should be highly acidic), possibly followed up by beta-F-elimination too -reaction via an actual oxonium ylide, i.e. dissociation of [LAg] from Int2  Fig5) is not an ylide (defined as a charge separation at neighboring atoms) as long as Ag is bound to that carbon, but it is referred to as an ylide all throughout the manuscript - Figure 1: I suggest clarifying the uncommon abbreviation Tfs in the caption - Figure 1, mechanism: the nucleophilic addition should be called just that and not "initiation", which is a term commonly associated with chain reactions. Also, the electron-pushing arrow should not originate from Ag but from its bond to C - Figure 4: please clarify the abbreviations DFHZ, TFHZ - Figure 5: please add the structure of Int1 - Figure 5, the first part of the mechanism should be referred to as nucleophilic addition -page 10, top: "these results suggest that the Ag catalyst plays a critical role [...] in the rearrangement process". Considering that the isolated intermediate 209 reacted to the product in 64% yield in the absence of Ag, the role cannot be so critical but rather supportive, please adjust the statement accordingly.
-page 10, middle/bottom: "Silver catalysis of a [3,3] rearrangement is, to our knowledge, without precedent". I don't know if this is really true but I don't think this is worth pointing out so much because I take it the reason is simply that Lewis-acid catalyzed rearrangements of this sort typically employ cheaper Lewis-acids than Ag-based ones.

REVIEWER COMMENTS
Reviewer #1 (Remarks to the Author): Bi and co-workers reported a formal selective C-F bond allylation/allenylation of trifluoromethylhydrazones by Ag-catalysis to access a diverse range of α,α-difluoroalkylketones featuring heterocycles or alkene/allene moiety. A cascading process including Ag-mediated defluorinative oxygenation and fluorine-Claisen rearrangement was supposed as the success of the reaction, which is distinct form the well-known single electron manifold employed for analogous transformation of trifluoromethyl carbonyls. Significantly broad substrate scope was demonstrated with respect to both of the coupling partners. Also, the gram scale reaction and elaboration of the products highlight the synthetic potency of this reaction. Interestingly, control experiments and DFT calculation reveal the dual role of Ag catalyst to enable the formation of gemdifluoroalkene intermediate and facilitate the subsequent Claisen rearrangement. Overall, this review supports the publication of manuscript in Nat. Commun., after some revisions were addressed.
(1) Does fluorine atoms exert a positive effect on the [3,3]-rearrangement of gem-difluorovinyl ether? Could the reaction proceed under the same conditions when replacing fluoride with chloride or bromide?
(3) In Figure 2, only indole, benzofurans, benzothiophenes, pyrrole, furan and thiophene derived carbinols were presented, what about substrates with greater degree of aromaticity, such as benzyl alcohol or naphthalene carbinol? (4) The authors are suggested to comment on the driving force for the [3,3]-rearrangement which destroy the aromaticity of the substrate. Why the dearomatized products did not undergo rearrangement spontaneously to regain aromaticity? (5) All presented alcohol substrates were primary and secondary alcohols, are tertiary alcohols viable substrates? (6) Aside from alcohols, are other nucleophiles, such as amine and thiol suitable for this carbene insertion/rearrangement cascade? (7) In the DFT part, the calculation result showed that the weak coordination of silver and oxygen could lower the energy barrier for the rate-determining rearrangement step. Could other stronger Lewis acids be applied instead of sliver to further reduce the rearrangement energy barrier, resulting in even milder reaction conditions for the [3,3]-rearrangement of gem-difluorovinyl ether? (8) While N-triftosylhydrazone substrates derived from alkyl trifluoromethyl ketones reacted with β,γunsaturated alcohols readily, no such a case was demonstrated in Fig. 2 when reacted with heteroaryl carbinols, why? (8) In cases 177-182, why Rh2(esp)2 exhibited higher efficiency than Tp Br3 Ag? Does any alkene product derived from deprotonation of silver carbene was observed? (9) In Feng's work (ACIE 2021, 60, 20237), the [3,3]-rearrangement tend to yield CF2-bridged 1,5-diene product. However, in this work, transformation of 3 to 198, gem-difluoroalkene was obtained as the rearranged product, please provide an explanation for this. (10) Last sentence of the abstract, "…in term of…" should be "… in terms of…".
Reviewer #2 (Remarks to the Author): Very recently the synthesis of fluorinated organic compounds using the acyl-CF3 compounds (CF3C(O)R) as fluorine source through carbodefluorination strategy has received a great attention and big progress has been made. But I think this strategy is meaningless because acyl-CF3 compounds are not easily prepared. That is: the introduction of fluorine atom into organic compounds was a challenging and hard, although the chemistry of the selective defluorination is interesting, the synthesis of new fluorinated compound through defluorination of fluorinated compounds was the waste of fluorine source. In this manuscript, Bi and coworkers described the carbodefluorination of acyl-CF3 compounds via fluoroalkyl N-triftosylhydrazones. This reaction proceeded though the silver-catalyzed sequential carbene generation, oxonium ylide formation, C-F bond cleavage, and eventual C-C bond formation through Claisen rearrangement of the resultant difluorovinyl ethers. A broad range of (hetero)aryl/alkyl fluoroalkyl ketones and β,γ-unsaturated alcohols were amenable to this reaction. This silver-catalyzed protocol provided single-step access to skeletally and functionally diverse α-mono-and α,αdifluoro-γ,δ-unsaturated ketones. The chemistry described in this manuscript is novel and interesting. Furthermore this manuscript was organized and written well. As I mentioned above, this method has less potential application in medicinal chemistry. But in light of the novelty of chemistry, I recommended for publication of this manuscript in Nature Communications when the following comments were addressed. 1) The title of this manuscript was too general. What kind of compound for carbodefluorination should be given.
2) How about the reaction of N-triftosylhydrazones derived from alkyl trifluoromethyl ketone with (hetero)aromatic carbinols, please give some examples.
3) Regarding to the reaction mechanism, the authors stated that gem-difluorinated vinyl ether was formed from the HF elimination of oxonium ylide. It may be formed from the elimiantion of AgF from oxonium ylide. Please confirm this by experiments.

Reviewer #3 (Remarks to the Author):
This manuscript by Bi and coworkers details a C-F functionalization of trifluoroacyl groups to a wide range of difluoro allyllic structures. The manuscript showcases the applicability of this reaction to construct an impressive and diverse range of structural motives by applying either various heterocycles, allylic alcohols or propargylic alcohols as reaction partners. The functional group tolerance of this transformation is good and a large amount of products was included in the scope to demonstrate the utility. A mechanism was proposed, that was also probed by DFT computations. From the synthetic point I recommend publication of this manuscript in Nature Comms, however, I do have some reservations about the computational aspects of this work in the current state. Mostly, the method combination B3LYP/6-31G(d,p) really is outdated for relative reaction (free) energies. Firstly, there is no reason not to apply empirical dispersion correction (D3) as it comes for free and has been shown countless times to systematically improve energies with B3LYP and many other functionals, particularly for non-covalent interactions. This is of relevance to this work because the authors invoke non-covalent interactions to explain parts of the mechanism. Moreover, energies at the double-zeta level are less accurate than those obtained with a larger basis set, which is why single point calculations on the stationary points with a triple-zeta basis set are the commonly used standard procedure. Thus, I urge the authors to improve the relative (free) energies for the reaction profile. Possibly this will not change the overall conclusions from the calculations, but it will make the reaction barriers that the authors also quote in the text much more reliable. Furthermore, I would appreciate the analysis of alternative reaction mechanisms in order to further back up the proposed mechanism. Alternatives that come to mind include: -beta-F-elimination from Int2 -deprotonation of Int2 (the O-H+ should be highly acidic), possibly followed up by beta-F-elimination too -reaction via an actual oxonium ylide, i.e. dissociation of [LAg] from Int2 Other more minor points: -In my understanding, the intermediate after nucleophilic addition (e.g. bottom row, middle in Fig 1 or Int2 in Fig5) is not an ylide (defined as a charge separation at neighboring atoms) as long as Ag is bound to that carbon, but it is referred to as an ylide all throughout the manuscript - Figure 1: I suggest clarifying the uncommon abbreviation Tfs in the caption - Figure 1, mechanism: the nucleophilic addition should be called just that and not "initiation", which is a term commonly associated with chain reactions. Also, the electron-pushing arrow should not originate from Ag but from its bond to C - Figure 4: please clarify the abbreviations DFHZ, TFHZ - Figure 5: please add the structure of Int1 - Figure 5, the first part of the mechanism should be referred to as nucleophilic addition -page 10, top: "these results suggest that the Ag catalyst plays a critical role [...] in the rearrangement process". Considering that the isolated intermediate 209 reacted to the product in 64% yield in the absence of Ag, the role cannot be so critical but rather supportive, please adjust the statement accordingly. -page 10, middle/bottom: "Silver catalysis of a [3,3] rearrangement is, to our knowledge, without precedent". I don't know if this is really true but I don't think this is worth pointing out so much because I take it the reason is simply that Lewis-acid catalyzed rearrangements of this sort typically employ cheaper Lewis-acids than Ag-based ones. Thank you very much for your suggestions. We have revised this manuscript according to your comments. The corrections in detail were given in the revised manuscript and were highlighted in yellow color. The detailed revision was listed as follows:

Recommendation: Accept
Comments: Bi and co-workers reported a formal selective C-F bond allylation/allenylation of trifluoromethylhydrazones by Ag-catalysis to access a diverse range of α,α-difluoroalkylketones featuring heterocycles or alkene/allene moiety. A cascading process including Ag-mediated defluorinative oxygenation and fluorine-Claisen rearrangement was supposed as the success of the reaction, which is distinct form the well-known single electron manifold employed for analogous transformation of trifluoromethyl carbonyls. Significantly broad substrate scope was demonstrated with respect to both of the coupling partners. Also, the gram scale reaction and elaboration of the products highlight the synthetic potency of this reaction. Interestingly, control experiments and DFT calculation reveal the dual role of Ag catalyst to enable the formation of gemdifluoroalkene intermediate and facilitate the subsequent Claisen rearrangement. Overall, this review supports the publication of manuscript in Nat. Commun., after some revisions were addressed.

Response:
We thank this reviewer for taking the time and effort to review our manuscript and give affirmation to this work.
1. Does fluorine atoms exert a positive effect on the [3,3]-rearrangement of gem-difluorovinyl ether? Could the reaction proceed under the same conditions when replacing fluoride with chloride or bromide?
Response: Many thanks for this valuable comment. According to the reviewer's suggestion, we tested the [3,3] rearrangement of gem-dichloroalkenyl ethers at different temperatures. The gem-dichloroalkenyl ether was converted to the rearranged product 212 in 82% and 4% yield at 80 °C and 40 °C, respectively. In contrast, the fluorine-substituted alkenyl ethers afforded rearranged product 86 in almost quantitative and 70% yield at 80 °C and 40 °C, respectively. These results indicated that the fluorine atom has a positive effect on the [3,3] rearrangement of the gem-difluoroalkenyl ethers. We have added the experimental results and spectra to the supplementary information.
Response: Thank you for pointing it out. The related work and reviews have been cited as Ref.48-53 in the revised manuscript.
3. In Figure 2, only indole, benzofurans, benzothiophenes, pyrrole, furan and thiophene derived carbinols were presented, what about substrates with greater degree of aromaticity, such as benzyl alcohol or naphthalene carbinol?
4. The authors are suggested to comment on the driving force for the [3,3]-rearrangement which destroy the aromaticity of the substrate. Why the dearomatized products did not undergo rearrangement spontaneously to regain aromaticity?
Response: Many thanks for the valuable suggestion. According to this suggestion, we have added related comments to the text as shown below: "The driving force to destroy the aromaticity of the substrate comes from the flow of electrons during the opening of the six-membered ring transition state during the [3,3]-rearrangement 61 ." The dearomatized products are stable enough to be isolated under column chromatography conditions, but they are easy to restore aromaticity under acidic conditions as shown in Figure 4d. This phenomenon was also observed in a recent work of [2,3] rearrangement of indole-based onium ylides (Nair, V. N. et al. J. Am. Chem. Soc. 2021, 143, 9016-9025).
5. All presented alcohol substrates were primary and secondary alcohols, are tertiary alcohols viable substrates?
Response: Thank you very much for the valuable questions. When tertiary alcohols were used as substrates, we observed less than 5% of the product 217, and 92% of the substrate was recovered. The possible reason is that the structure of the tertiary alcohol has a larger resistance. These results were summarized in supplementary information. The related comments were added to the text as shown below: "However, we observed that tertiary alcohols are not suitable for this transformation, possibly because the structures of tertiary alcohols are more sterically hindered during electrophilic attack." 6. Aside from alcohols, are other nucleophiles, such as amine and thiol suitable for this carbene insertion/rearrangement cascade?
Response: Many thanks for this comment. Other nucleophiles, such as allylamines and allylthiols, are also suitable for this carbene insertion/rearrangement cascade. The related investigations are ongoing in our laboratory and will be reported in another paper.
7. In the DFT part, the calculation result showed that the weak coordination of silver and oxygen could lower the energy barrier for the rate-determining rearrangement step. Could other stronger Lewis acids be applied instead of sliver to further reduce the rearrangement energy barrier, resulting in even milder reaction conditions for the [3,3]-rearrangement of gem-difluorovinyl ether?
Response: The reviewer's assumption is right. We first used Lewis acids stronger than silver as the catalysts, such as BF3•Et2O, AlCl3, to catalyze [3,3] rearrangement of gem-difluoroalkenyl ethers under mild conditions (40 o C). The results show that both BF3•Et2O and AlCl3 are better catalyst than Tp Br3 Ag, and the rearrangement product 86 is obtained in 72% and 75% yields. In addition, the rearrangement product was only obtained in 11% yield without catalyst. Therefore, the use of strong Lewis acids instead of silver can reduce the rearrangement energy barrier, allowing [3,3] rearrangements to be carried out under milder conditions. Afterwards, we used BF3▪Et2O and AlCl3 to catalyze the the carbodefluorination reaction. The results showed that compound 86 could not be obtained. This illustrates that the dual role of Tp Br3 Ag (metal carbene catalyst and Lewis acid catalyst) for the carbodefluorination reaction is necessary. Furthermore, I would appreciate the analysis of alternative reaction mechanisms in order to further back up the proposed mechanism. Alternatives that come to mind include: